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Randomized Controlled Trial
. 2022 Nov;27(11):975-982.
doi: 10.1111/resp.14326. Epub 2022 Jul 10.

Atomoxetine and fesoterodine combination improves obstructive sleep apnoea severity in patients with milder upper airway collapsibility

Ludovico Messineo  1 , Luigi Taranto-Montemurro  1 , Nicole Calianese  1 , Laura K Gell  1 , Ali Azarbarzin  1 , Gonzalo Labarca  1 , Dan Vena  1 , Hyung Chae Yang  1 , Tsai-Yu Wang  1 , Andrew Wellman  1 , Scott A Sands  1   2
Affiliations
Randomized Controlled Trial

Atomoxetine and fesoterodine combination improves obstructive sleep apnoea severity in patients with milder upper airway collapsibility

Ludovico Messineo et al. Respirology. 2022 Nov.

Abstract

Background and objective: The combination of the noradrenergic atomoxetine plus the anti-muscarinic oxybutynin acutely increased genioglossus activity and reduced obstructive sleep apnoea (OSA) severity. However, oxybutynin has shorter half-life than atomoxetine and side effects that might discourage long-term usage. Accordingly, we aimed to test the combination of atomoxetine and fesoterodine (Ato-Feso), a newer anti-muscarinic with extended release formulation, on OSA severity and endotypes.

Methods: Twelve subjects with OSA underwent a randomized, double-blind, crossover trial comparing one night of atomoxetine plus fesoterodine (80-4 mg) to placebo. Parameters of OSA severity (e.g., apnoea-hypopnoea index [AHI], nadir oxygen desaturation and hypoxic burden) were calculated from two clinical, in-lab polysomnographic studies. OSA endotypes (including collapsibility per VMIN and arousal threshold) were derived from validated algorithms.

Results: Compared to placebo, Ato-Feso did not reduce the AHI (34.2 ± 19.1 vs. 30.1 ± 28.2 events/h, p = 0.493), but reduced the apnoea index (12.9 [28.8] vs. 1.8 [9.1] events/h, median [interquartile range], p = 0.027) and increased nadir desaturation (76.8 [8.0] vs. 82.2 [8.8] %, p = 0.003); a non-significant trend for improved hypoxic burden was observed (52.4 [50.5] vs. 29.7 [78.9] %min/h, p = 0.093). Ato-Feso lowered collapsibility (raised VMIN ; 43.7 [29.8-55.7] vs. 56.8 [43.8-69.8] %VEUPNOEA , mean [CI], p = 0.002), but reduced the arousal threshold (129.3 [120.1-138.6] vs. 116.7 [107.5-126] %VEUPNOEA , p = 0.038). In post hoc analysis, 6/6 patients with milder collapsibility (VMIN > 43%) exhibited OSA resolution (drop in AHI > 50% and residual AHI < 10 events/h) and improved hypoxaemia.

Conclusion: While inefficacious in unselected patients, Ato-Feso administered for one night suppressed OSA in patients with milder collapsibility. Ato-Feso may hold some promise as an alternative OSA treatment in certain subgroups of individuals.

Keywords: Ato-Feso; Ato-Oxy; atomoxetine; fesoterodine; obstructive sleep apnoea; upper airway collapsibility.

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Conflict of interest statement

AA receives grant support from Somnifix and serves as consultant for Somnifix, Inspire, and Apnimed; SS receives personal fees as a consultant for Nox Medical, Apnimed, Merck, Lilly, and Inspire outside the submitted work, and has received grant support from Apnimed, Prosomnus, and Dynaflex; AW works as a consultant for Apnimed, Somnifix, and Nox Medical and he has received grants from Somnifix and Sanofi. LTM and AW have a financial interest in Apnimed, a company developing pharmacologic therapies for sleep apnea. Their interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies; LTM is the Chief Scientific Officer at Apnimed.

Figures

Figure 1.
Figure 1.
CONSORT diagram that shows recruitment, randomization, and analysis procedures for the trial.
Figure 2.
Figure 2.
Left: VMIN on placebo was associated with Ato-Feso efficacy (Pearson’s correlation). Responders (red box) exhibited milder collapsibility, characterized by a VMIN above 43%VEUPNEA (blue vertical line, median level). Right: Endogram plot of ventilation versus estimated ventilatory drive in an example patient. VMIN (blue dot) describes ventilation at minimal ventilatory drive (i.e. maximally passive conditions). VPASSIVE (purple dot) represents ventilation at eupneic drive, while VACTIVE (red dot) describes ventilation when muscle are active (i.e. at arousal threshold, vertical green line). The orange area represents the IQR.
Figure 3.
Figure 3.
A. OSA severity was not systematically changed by the acute administration of Ato-Feso. Horizontal bars denote mean values. B Post-hoc analysis revealed that OSA severity in patients with greater collapsibility (identified by VMIN<43%VEUPNEA) was not different between the nights. C. However, OSA severity in patients with milder collapsibility (VMIN>43%VEUPNEA) was significantly reduced by Ato-Feso administration. Horizontal bars in B and C denote median values.
See this image and copyright information in PMC

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